Most cancer deaths are caused by metastases, which are secondary tumors from cancer cells or clusters of such cancer cells that have broken off from the primary tumor and now are surviving at a distant site. Often these exist as micrometastases consisting of one or a few cells that are not growing or are growing very slowly or divide only at a rate sufficient for replacement thereof. Eventually, after some years or even decades, some of the micrometastases may begin to grow rapidly, forming tumors which eventually kill the patient. Micrometastases are notoriously resistant to traditional chemotherapeutic agents because the cells are not actively growing or expressing the malignant phenotype.
Currently, the drug development system for developing anticancer drugs is based on finding compounds that kill growing tumors. The initial step in developing an anticancer drug involves the screening of compounds against cancer cells growing in ordinary tissue culture on plastic. In vitro growth on plastic neglects the true physiological conditions under which tumors grow in the body, i.e., in contact with extracellular matrix. The extracellular matrix (ECM) in living tissues is the supporting material on which all cells grow and which interacts with cells to regulate their growth and how they assume their mature functions. Cancer cells remodel the extracellular matrix to be more conducive to growth of the cancer cells, and this process seems to represent a major requirement for them to be able to form a tumor.
For example, about 60,000 new cases of bladder cancer occur each year in the U.S. with about 13,000 deaths, placing it 5th overall in cancer incidence. In the United States, 98% of bladder cancers arise from the transitional epithelium of the bladder (transitional cell carcinoma, i.e., TCC). The general perception that bladder cancer is not serious is false. Some 15-25% of cases are invasive at diagnosis with one-fourth already having metastasized and with up to half developing metastatic tumors within two to three years. The 5-year survival of patients with metastatic bladder cancer is very low, about 20% with about a six-month median survival for even the most aggressive therapies. Of the 80-85% that are papillary, recurrence is high, up to 70% within 5 years in some studies, and of these, some 15%-25% will progress to invasive bladder cancer. Therapy achieves few cures, whether with BCG chemotherapy or neoadjuvant chemotherapy. The reasons for the high recurrence rate of bladder cancer are not known entirely, however, three mechanisms are suggested including underdiagnoisis by cystoscopy, a widespread “field defect” with continued promotion of new tumors or suppression of malignant cells, preventing their growth for a time.
To this end, the present invention is directed to novel in vitro and in vivo methods for identifying compounds capable of targeting living, phenotypically suppressed cancer cells, in particular, micrometastatic cells.